title: Fetal inflammatory response in women with proteomic biomarkers characteristic of intra-amniotic inflammation and preterm birth.
abstract: OBJECTIVE
  To determine the relationship between presence of amniotic fluid (AF) biomarkers characteristic of inflammation (defensins 2 and 1 and calgranulins C and A) and fetal inflammatory status at birth.
  
  
  METHODS
  Prospective observational cohort.
  
  
  METHODS
  Tertiary referral University hospital.
  
  
  METHODS
  One hundred and thirty-two consecutive mothers (gestational age, median [interquartile range]: 29.6 [24.1-33.1] weeks) who had a clinically indicated amniocentesis to rule out infection and their newborns.
  
  
  METHODS
  Intra-amniotic inflammation was diagnosed by mass spectrometry surface-enhanced-laser-desorption-ionization time of flight (SELDI-TOF). The AF proteomic fingerprint (mass-restricted [MR] score) ranges from 0-4 (none to all biomarkers present). The intensity of intra-amniotic inflammation was graded based on the number of proteomic biomarkers: MR score 0: 'no' inflammation, MR score 1-2: 'minimal' inflammation and MR score 3-4: 'severe' inflammation. At birth, cord blood was obtained for all women. Severity of histological chorioamnionitis and early-onset neonatal sepsis (EONS) was based on established histological and haematological criteria. Interleukin-6 (IL-6) levels were measured by sensitive immunoassays. The cord blood-to-AF IL-6 ratio was used as an indicator of the differential inflammatory response in the fetal versus the AF compartment.
  
  
  METHODS
  To relate proteomic biomarkers of intra-amniotic infection to cord blood IL-6 and to use the latter as the primary marker of fetal inflammatory response.
  
  
  RESULTS
  Women with intra-amniotic inflammation delivered at an earlier gestational age (analysis of variance, P<0.001) and had higher AF IL-6 levels (P<0.001). At birth, neonates of women with severe intra-amniotic inflammation had higher cord blood IL-6 levels (P=0.002) and a higher frequency of EONS (P=0.002). EONS was characterised by significantly elevated cord blood IL-6 levels (P<0.001). Of the 39 neonates delivered by mothers with minimal intra-amniotic inflammation, 15 (39%) neonates had umbilical cord blood IL-6 levels above the mean for the group and 2 neonates had confirmed sepsis. The severity of the neutrophilic infiltrate in the chorionic plate (P<0.001), choriodecidua (P=0.002), umbilical cord (P<0.001) but not in the amnion (P>0.05) was an independent predictor of the cord blood-to-AF IL-6 ratio. Relationships were maintained following correction for gestational age, birthweight, amniocentesis-to-delivery interval, caesarean delivery, status of the membranes, race, MR score and antibiotics and steroid exposure.
  
  
  CONCLUSIONS
  We provide evidence that presence of proteomic biomarkers characteristic of inflammation in the AF is associated with an increased inflammatory status of the fetus at birth. Neonates mount an increased inflammatory status and have positive blood cultures even in the context of minimal intra-amniotic inflammation.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA. catalin.buhimschi@yale.edu
authors.forename: C S
authors.initials: CS
authors.lastname: Buhimschi
authors.forename: A T
authors.initials: AT
authors.lastname: Dulay
authors.forename: S
authors.initials: S
authors.lastname: Abdel-Razeq
authors.forename: G
authors.initials: G
authors.lastname: Zhao
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.forename: E J
authors.initials: EJ
authors.lastname: Hodgson
authors.forename: V
authors.initials: V
authors.lastname: Bhandari
authors.forename: I A
authors.initials: IA
authors.lastname: Buhimschi
mesh_terms: D000328:Adult; D000653:Amniotic Fluid / Q000276:immunology; D000704:Analysis of Variance; D015415:Biomarkers / Q000032:analysis; D002821:Chorioamnionitis / Q000175:diagnosis*; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000175:diagnosis*; D047928:Premature Birth / Q000276:immunology*; D011446:Prospective Studies; D020543:Proteome / Q000032:analysis; D012044:Regression Analysis
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D020543:Proteome